Novel parenteral carbamazepine formulation

ABSTRACT

The present invention is directed to a carbamazepine-cyclodextrin inclusion complex useful for the parenteral administration of carbamazepine. The carbamazepine-cyclodextrin inclusion complex is prepared by the admixture of a modified cyclodextrin and carbamazepine in a physiologically acceptable fluid. Modified cyclodextrins include 2-hydroxypropyl-beta-cyclodextrin and sulfoalkyl cyclodextrins. More particularly, the sulfoalkyl cyclodextrins are those described and disclosed in U.S. Pat. Nos. 5,134,127 and 5,376,645. A physiologically acceptable fluid includes sterile isotonic water, Ringer&#39;s lactate, D5W (5% dextrose in water), physiological saline, and similar fluids suitable for parenteral administration.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/547,866, filed Jul. 12, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/571,039, filed Sep. 30, 2009, which is acontinuation of U.S. patent application Ser. No. 11/542,520, filed Oct.2, 2006, which was filed concurrently with International Application No.PCT/US2006/038508, filed Oct. 2, 2006, and which claims priority fromProvisional Patent Application No. 60/722,692, filed Sep. 30, 2005. Eachof the aforementioned applications are hereby incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

Carbamazepine, or 5H-dibenz[b,f]azepine-5-carboxamide, is a widely usedantiepileptic agent. It is available in the U.S. as Tegretol brandchewable tablets of 100 mg, tablets of 200 mg and suspension of 100 mg/5mL, intended for oral administration as a treatment for epilepsy or as aspecific analgesic for trigeminal neuralgia. Other brand names includeEquetro, Carbatrol, Tegretol XR and Epitol. Generic versions of theseoral dosage forms are also available. Dosage forms include Carbatrolavailable in 100, 200, and 300 mg strengths; and Tegretol XR, availablein 100, 200, and 400 mg strengths.

As shown in Table 1, recommended maintenance dosage levels in adults andchildren over 12 years of age are 800-1200 mg daily, although up to 2400mg daily have been used in adults. In children of 6 to 12 years of age,the maintenance dosage level is usually 20-30 mg/kg/d and in childrenless than 6 years old the maintenance dosage level is usually 10-20mg/kg/d.

TABLE 1 Labeled dosage for carbamazepine oral dosage forms. RecommendedDosing Frequency Daily (for IR Age Maintenance Dose formulations)   <6yrs 10-20 mg/kg 2-4 doses/day 6-12 yrs 20-30 mg/kg 2-4 doses/day maxdose 1000 mg Children >12 yrs 400-1200 mg 2-4 doses/day 1600-2400 mgAdults-epilepsy 800-1200 mg 3-4 divided doses some pts require 1600-2400mg Adults- 400-800 mg   2 doses/day trigeminal max dose 1200 mgneuralgia Adults-bipolar Doses greater   2 doses/day disorder than 1600mg have not been studied Note: only Equetro, an extended releaseformulation is approved for bipolar disorder.

For complex partial seizures (temporal lobe, psychomotor), carbamazepineis a widely used anticonvulsant drug. It is also of proven efficacy inthe treatment of generalized tonic-clonic (grand mal) seizures.Carbamazepine has also been used in treating simple partial (focal orJacksonian) seizures and in patients with mixed seizure patterns whichinclude the above, or other partial or generalized seizures. It is notused in the treatment of absence seizures (petit mal).

In addition to its proven effectiveness, carbamazepine has, in manyrespects, a more favorable profile in terms of the incidence andseverity of side-effects than other anticonvulsants. Thus, carbamazepineis less sedating and causes less intellectual function impairment thanother antiepileptic drugs such as phenobarbital, primidone andphenytoin. Furthermore, carbamazepine does not precipitate gingivalhypertrophy, hirsutism, acne or other undesired effects associated withphenytoin. These attributes have helped to make carbamazepine the drugof choice in women and children.

Use of carbamazepine is complicated by incomplete, slow and variableabsorption; extensive protein binding; and induction of its ownmetabolism. From Spina E Chapter 21 in Antiepileptic Drugs 5th edition.Lippincott, Williams & Wilkins, Philadelphia, 2002 pp 236-246 andreferences cited therein. The absolute bioavailability (the percentageof a dose that reaches the bloodstream) for the immediate release andextended release tablets has previously been estimated to range from75-85 although the absence of an intravenous formulation has precludedsystematic study of the extent and inter-patient variability inabsorption.

U.S. Pat. No. 5,231,089 to Bodor mentions the lack of an injectableformulation for carbamazepine, noting that therefore there has not beenprecise information relating to the drug's absolute bioavailability. Inaddition, the lack of an injectable formulation for carbamazepine meansthat there is no method for providing emergent carbamazepine therapy toa patient in need thereof, as occurs when patients are undergoingsurgery, have certain gastro-intestinal diseases, are unconscious orhave seizures that preclude oral drug administration, or that requirerapid re-establishment of steady state plasma levels.

The absence of an intravenous formulation places patients treated withcarbamazepine (sometimes referred to herein as CBZ) at substantialmedical risk. Sudden discontinuation of CBZ therapy for whatever reason,can expose an individual to potentially life threatening seizureemergencies. The only alternative is to give the patient a differentdrug that is available as an intravenous formulation. Exposure to a newmedications exposes the patient to adverse reactions and unknownefficacy.

Cyclodextrins, sometimes referred to as Schardinger's dextrins, werefirst isolated by Villiers in 1891 as a digest of Bacillus amylobacteron potato starch. The foundations of cyclodextrin chemistry were laiddown by Schardinger in the period 1903-1911. Until 1970, however, onlysmall amounts of cyclodextrins could be produced in the laboratory andthe high production cost prevented the usage of cyclodextrins inindustry. In recent years, dramatic improvements in cyclodextrinproduction and purification have been achieved and cyclodextrins havebecome much less expensive, thereby making the industrial application ofcyclodextrins possible.

Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on theouter surface and a void cavity in the center. Their outer surface ishydrophilic, and therefore they are usually soluble in water, but thecavity has a lipophilic character. The most common cyclodextrins areα-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, consisting of 6,7 and8 α-1,4-linked glucose units, respectively. The number of these unitsdetermines the size of the cavity.

Cyclodextrins are capable of forming inclusion complexes with a widevariety of hydrophobic molecules by taking up a whole molecule (a “guestmolecule”), or some part of it, into the void cavity. The stability ofthe resulting complex depends on how well the guest molecule fits intothe cyclodextrin cavity. Common cyclodextrin derivatives are formed byalkylation (e.g., methyl-and-ethyl β-cyclodextrin) or hydroxyalkylationof the hydroxyethyl-derivatives of α-, β-, and γ-cyclodextrin) or bysubstituting the primary hydroxyl groups with saccharides (e.g.,glucosyl- and maltosyl-β-cyclodextrin). Hydroxypropyl-β-cyclodextrin andits preparation by propylene oxide addition to β-cyclodextrin, andhydroxyethyl-β-cyclodextrin and its preparation by ethylene oxideaddition to β-cyclodextrin, were described in a patent of Gramera et al.(U.S. Pat. No. 3,459,731, issued August 1969) over 35 years ago.

Although cyclodextrins have been used to increase the solubility,dissolution rate and/or stability of a great many compounds, it is alsoknown there are many drugs for which cyclodextrin complexation either isnot possible or yields no advantages. See J. Szejtli, Cyclodextrins inDrug Formulations: Part II, Pharmaceutical Technology, 24-38, August,1991. Despite this potential pharmaceutical utility, certaincyclodextrins are have limitations.

Cyclodextrins and their derivatives are mostly crystalline solids.Concentration of some cyclodextrins in the renal tissue is followed bycrystal formation causing necrotic damage to the cells. Despite formingwater soluble clathrate complexes, the crystalline cyclodextrin drugcomplexes have generally been limited in their utility to sublingual ortopical administration.

U.S. Pat. Nos. 5,134,127 and 5,376,645, whose disclosures areincorporated herein by reference, are directed to novel cyclodextrinderivatives, in particular sulfoalkyl cyclodextrin derivatives, thatovercome the limitations of other cyclodextrins. In particular, thesulfoalkyl cyclodextrin derivatives disclosed therein exhibit lowernephrotoxicity while exhibiting high aqueous solubility.

The present invention is based, inter alia, on the determination thatcarbamazepine stable inclusion complexes with cyclodextrins are highlywater soluble relative to the non-complexed drug. Surprisingly andunexpectedly, the carbamazepine-cyclodextrin inclusion complexes of theinvention result in an injectable formulation that provides significantbenefits and advantages over other carbamazepine formulations. Forexample, the carbamazepine-cyclodextrin inclusion complexes of thepresent invention are completely bioavailable, delivering 100% of thedose to the bloodstream in a consistent and predictable manner which isnot the case with solid oral dosage forms. Also, unlike solid oraldosage forms, the carbamazepine-cyclodextrin inclusion complexes of thepresent invention can be administered to a patient suffering from ageneralized tonic-clonic or other acute seizure via a peripheral ratherthan oral route. The carbamazepine-cyclodextrin inclusion complexes ofthe present invention satisfy a significant unmet medical need for astable injectable formulation of carbamazepine that overcomes thelimitations of poorly soluble and variably absorbed oral formulations.

SUMMARY OF THE INVENTION

In one aspect, the present invention contemplates acarbamazepine-cyclodextrin inclusion complex useful for the parenteraladministration of carbamazepine comprising a carbamazepine complexedwith a modified cyclodextrin. Preferably, the modified cyclodextrin is asulfoalkyl-cyclodextrin. A preferred modified cyclodextrin issulfobutylether-7-beta-cyclodextrin. The inclusion complex preferablyhas a concentration of about 5 to about 50 mg/ml carbamazepine, and morepreferably a concentration of about 10 mg/ml carbamazepine.

In another aspect, the present invention, there is provided acarbamazepine-cyclodextrin inclusion complex useful for the parenteraladministration of carbamazepine in which dosing is about 30% to about100% of oral maintenance doses, or preferably about 65% to 75% of oralmaintenance doses.

In a further aspect, the present invention provides acarbamazepine-cyclodextrin inclusion complex useful for the parenteraladministration of carbamazepine having a half-life of about 8 to about65 hours, and more preferably having a half-life of about 24 hours. Inanother embodiment, the present invention contemplates acarbamazepine-cyclodextrin inclusion complex useful for the parenteraladministration of carbamazepine having an area under the plasmaconcentration-time curve (AUC) of about 70% to about 130% of the AUC foran oral carbamazepine dosage form, and more preferably having an AUC ofabout 80% to about 125% of the AUC for an oral carbamazepine dosageform. In a further embodiment, the present invention contemplates acarbamazepine-cyclodextrin inclusion complex useful for the parenteraladministration of carbamazepine having a minimum plasma concentration(Cmin) of about 70% to about 130% of the Cmin for an oral carbamazepinedosage form, and more preferably having a Cmin of about 80% to about125% of the Cmin for an oral carbamazepine dosage form.

In a still further aspect, the present invention provides acarbamazepine-cyclodextrin inclusion complex useful for the parenteraladministration of carbamazepine having an intravenous dosing interval ofevery four to twelve hours, more preferably having an intravenous dosinginterval of every six hours, and still more preferably having anintravenous dosing interval of every eight hours.

In another embodiment the present invention provides a method ofadministering a carbamazepine-cyclodextrin inclusion complex useful forthe parenteral administration of carbamazepine comprising: 1) providinga carbamazepine-cyclodextrin inclusion complex; and 2) infusing thecomplex intravenously to a patient in need thereof every four to twelvehours.

Preferably, the period of infusing occurs over about 5 to about 60minutes, more preferably over 30 minutes and still more preferably over5 minutes. Preferably, the infusing is done every six hours, or inanother aspect every eight hours.

In a still further embodiment, the present invention provides a methodof preparing a carbamazepine-cyclodextrin inclusion complex by admixinga modified cyclodextrin and carbamazepine in a physiologicallyacceptable fluid to form a carbamazepine-cyclodextrin inclusion complex.In another aspect, the method further includes the step of sterilizingthe carbamazepine-cyclodextrin inclusion complex. Preferably, thephysiologically acceptable fluid is isotonic. Preferably, the modifiedcyclodextrin is a sulfoalkyl-cyclodextrin. The modified cyclodextrin ismore preferably sulfobutylether-7-beta-cyclodextrin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows carbamazepine phase solubility as a function ofcyclodextrin concentration at ambient laboratory temperature. FIG. 1Arepresents the compiled solubility data. FIG. 1B represents the averagedsolubility data.

FIG. 2 shows the DSC/TGA overlay of Carbamazepine Orgamol batch #899954.

FIG. 3 shows the DSC/TGA overlay of Carbamazepine Spectrum batch#SA0491.

FIG. 4 shows the observed and predicted plasma concentration-timeprofiles following intravenous administration of 100 mg of carbamazepineusing a 3-compartment PK model.

FIG. 5 shows the simulated plasma concentration-time profiles ofcarbamazepine following different infusion durations. The mean IVdose=150 mg, the average adjusted IV dose assuming F=0.7. Modelparameters are the typical values parameters from the three-compartmentmodel.

FIG. 6 shows the effect of infusion duration on Cmax,ss following IVadministration of carbamazepine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a carbamazepine-cyclodextrininclusion complex useful for the parenteral administration ofcarbamazepine.

As used herein, the term “parenteral” is given its ordinary andcustomary meaning in the field of pharmaceutical drug routes ofadministration. According to the Food and Drug Administration's Centerfor Drug Evaluation and Research Data Standards Manual (CDER DataElement Number C-DRG-00301; Data Element Name: Route of Administration)“parenteral” refers to administration by injection, infusion orimplantation. Injection and infusion include administration into a vein(intravenous), into an artery (intraarterial), into a muscle(intramuscular), under the skin (subcutaneous), and into the peritoneum(intraperitoneal). Intrapulmonary (administration within the lungs orits bronchi) and nasal (administration into the nose or by way of thenose) is also contemplated. Any appropriate route of administration setforth in the above-referenced Food and Drug Administration document isspecifically included within the scope of the instant invention, andnothing herein shall be construed to limit in any way those routes ofadministration that would be useful in connection with thecarbamazepine-cyclodextrin inclusion complex of the present invention.

In one embodiment, the carbamazepine-cyclodextrin inclusion complex isprepared by the admixture of a modified cyclodextrin and carbamazepinein a physiologically acceptable fluid. Modified cyclodextrins include2-hydroxypropyl-beta-cyclodextrin and sulfoalkyl cyclodextrins. Moreparticularly, the sulfoalkyl cyclodextrins are those described anddisclosed in U.S. Pat. Nos. 5,134,127 and 5,376,645. A physiologicallyacceptable fluid includes sterile isotonic water, Ringer's lactate, D5W(5% dextrose in water), physiological saline, and similar fluidssuitable for parenteral administration.

After an admixture of the modified cyclodextrin and carbamazepine isprepared, the admixture can be sterilized. Sterilization can be bymethods well known to those of ordinary skill in the art, such as byautoclaving or by sterile filtration such as passage through a 0.22micron filter. After-sterilization, the carbamazepine-cyclodextrininclusion complex can be directly packaged into sterile ampoules,containers for fluids suitable for intravenous administration, or thecomplex can be lyophilized for prolonged storage according to techniqueswell known in the art.

The carbamazepine-cyclodextrin inclusion complex can be prepared so thatthe concentration of carbamazepine ranges from 1 mg/ml to 50 mg/ml, morepreferably from 1 mg/ml to 10 mg/ml, and most preferably about 10 mg/ml.Variations in the carbamazepine concentration in thecarbamazepine-cyclodextrin inclusion complex of the present invention isconventionally accomplished by varying the amount of carbamazepine usedin the preparation of that inclusion complex, as described elsewhereherein.

The carbamazepine-cyclodextrin inclusion complex can be administeredparenterally in a single dose of up to 1600 mg, or preferably up to 500mg, more preferably divided doses from 20 to 500 mg, and most preferablydivided doses from 75 to 400 mg. Dosing is dependent upon the indicationof the patient being treated, as well as interactions with other drugsthat the patient can be taking, and other clinical considerations wellwithin the skill of the attending physician.

The carbamazepine-cyclodextrin inclusion complex of the presentinvention has a bioavailability of 100% and a half-life of about 24hours. Resultant plasma concentrations after intravenous administrationare reasonably predictable with every 1 mg/kg dose producing an increasein CBZ concentration of 0.75.+−.0.2 mg/L. Given an average oralbioavailability of 65-75%, the initial IV replacement dose will be65-75% of a patient's maintenance dose although some adjustment insubsequent IV doses may be necessary depending on a patient's actualoral CBZ bioavailability. This dosing regimen is selected in order toensure that trough CBZ concentrations remain within the therapeuticrange, while minimizing the risk of adverse events associated withelevated, end-of-infusion of CBZ concentrations.

The carbamazepine-cyclodextrin inclusion complex of the presentinvention preferably has certain pharmacokinetic parametersstatistically similar to those of oral CBZ dosage forms. For example,the carbamazepine-cyclodextrin inclusion complex preferably has aminimum plasma concentration (Cmin) of about 70% to about 130% of theCmin of an oral CBZ dosage form, and more preferably from about 80% toabout 125% of the Cmin of an oral CBZ dosage form. Similarly, thecarbamazepine-cyclodextrin inclusion complex has an area under theplasma concentration-time curve (AUC) of about 70% to about 130% of theAUC of an oral CBZ dosage form, and more preferably from about 80% toabout 125% of the AUC of an oral CBZ dosage form. Workers of ordinaryskill in the art of pharmaceutical formulation are well acquainted withthese concepts, which are further explained in the Food and DrugAdministrations' Guidance for Industry entitled “Statistical Approachesto Establishing Bioequivalence” of January 2001 (see the world wide webfda.gov/cder/guidance/3616fnl.htm.)

The total daily intravenous (IV) dose can be administered as four equaldoses every six hours, infused over up to 60 minutes, or preferably over30 minutes, or more preferably over 15 minutes. As is well known in theart, the infusion duration and dosing interval can be adjusted dependingupon clinical considerations within the skill of the attendingphysician. For example, in a situation where rapid return tosteady-state levels of CBZ is desired, the infusion duration can be asshort as 2-5 minutes via IV push or IV bolus administration to a patientin need thereof. In other embodiments, the total daily IV dose can beadministered as three equal doses every eight hours, infused over up to60 minutes, or preferably over 30 minutes, or more preferably over 15minutes. In further embodiments, administration can be continuous, orcan be administered using a patient controlled device that permitscontrolled dosing on an as needed basis. Other dosing schedules are wellknown in the art, and can be readily determined by pharmacists andphysicians skilled in the art based upon considerations of, for example,age of the patient, indication, divided dose and total daily dosage.

In other embodiments, the carbamazepine-cyclodextrin inclusion complexesof the present invention can be administered via rectal, oral or nasalroutes for those patients who either cannot tolerate parenteraladministration or who are so young that parenteral administration is notpractical. In addition, those patients who can receive the formulationof the present invention via an enteral route will obtain the benefitsof substantially complete bioavailability over present sold oral dosageforms. Enteral administration does not require a change in theformulation of the present invention, as thosecarbamazepine-cyclodextrin inclusion complexes can be directly deliveredenterally. Taste masking formulations, well known in the art, can beused to modify formulations designed to be administered orally toeliminate any unpleasant taste. Taste masking is, however, related topatient compliance rather than related to efficacy of the presentinvention for enteral administration.

The carbamazepine-cyclodextrin inclusion complexes of the presentinvention can be administered to a mammal in need of CBZ treatment. Theword “mammal” is given its ordinary and customary meaning in the art,and includes human beings. Accordingly, the carbamazepine-cyclodextrininclusion complexes of the present invention can be used in veterinaryapplications as well as the treatment of human conditions. With respectto human treatment, the carbamazepine-cyclodextrin inclusion complexesof the present invention is particularly well suited for pediatricadministration, because the instant formulation does not require aperoral route of administration.

The carbamazepine-cyclodextrin inclusion complexes of the presentinvention can be used for any indication for which CBZ is used. Forexample, CBZ is indicated for seizure disorders such as partial seizureswith complex symptoms (psychomotor, temporal lobe epilepsy), generalizedtonic-clonic (grand mal) seizures, mixed seizure patterns or otherpartial or generalized seizures. CBZ is also indicated for trigeminalneuralgia (tic douloureux) such as treatment of pain associated withtrue trigeminal neuralgia and bipolar disorders. CBZ is also beneficialin glossopharyngeal neuralgia. Other uses include treatment ofneurogenic diabetes insipidus; certain psychiatric disorders, includingschizoaffective illness, depression, agitation, behavioral disturbancesrelated to dementia, resistant schizophrenia, and dyscontrol syndromeassociated with limbic system dysfunction; alcohol withdrawal;fibromyalgia; neuropathy; status epilipticus; and refractory seizuredisorders.

While the carbamazepine-cyclodextrin inclusion complexes of the presentinvention provide reduced toxicity and 100% bioavailability compared toother parenteral carbamazepine formulations such as a PEG400formulation. Moreover, the complexes of the present invention are lessnephrotoxic while providing similar solubilities and dissolution ratesof carbamazepine-cyclodextrin complexes.

Further details of the preferred embodiments of the present inventionare illustrated in the following examples, which are understood to benon-limiting.

EXAMPLES Example 1 Preparation of Carbamazepine-Cyclodextrin InclusionComplex

450 Grams of hydroxypropyl-beta-cyclodextrin (HPBCD) was dissolved in2.0 L of deionized water to generate a 22.50 w/v solution. ¹³C,¹⁵N-labeled carbamazepine (CBZ) [purchased from Cambridge IsotopeLaboratories (CIL), 50 Frontage Road, Andover, Mass. 01810], 20 grams,was added to this solution. The resulting admixture was stirred for 24hours at room temperature (20-25° C.). After 24 hours, the solution wassterile filtered through a sterile 0.22 micron Durapore filter into asterile receiver. Previously sterilized ampoules were then filled andsealed under a nitrogen flush. The filled ampoules were stored at 2-8°C. The resulting inclusion complex had a CBZ concentration ofapproximately 10 mg/ml.

Example 2 Stability Testing

Ampoules containing 10.1 mg/ml carbamazepine-cyclodextrin inclusioncomplex were placed on room temperature stability studies and sampledevery six months. CBZ was detected by HPLC using UV detection at 215 nm.Results are presented in Table 2.

TABLE 2 Stability of Intravenous, Stable-labeled Carbamazepine SolutionInitial Degradation Testing Concentration % Product- CBZ: Date in VialRecovery iminostilbine May 31, 2005 10.1 mg/ml 104.65% not detected Nov.10, 2004 10.1 mg/ml 97.07% not detected May 2, 2004 10.1 mg/ml 96.67%not detected

Example 3 Pharmacokinetics of Intravenous and Oral Carbamazepine inPatients on Maintenance Therapy

Indwelling catheters were placed into the arms of test subjects. Asingle 100 mg dose of stable-labeled (non-radioactive) CBZ (SL-CBZ) wasthen infused over 10 minutes. At the end of the infusion, the subject'susual morning dose of oral CBZ, less 100 mg, was administered. Bloodpressure, heart rate and rhythm, and infusion site discomfort weremonitored during and for an hour after the infusion. A single bloodsample was collected prior to the infusion and 12 samples were collectedover the ensuing 96 hours. Plasma was separated from blood and analyzed,using a LC-MS assay, for CBZ and CBZ-epoxide, an active metabolite, andglucuronidated metabolite that is inactive. Unbound CBZ was measuredfollowing ultrafiltration. CBZ concentration-time data were analyzedusing a non-compartmental approach with the pharmacokinetic software,WinNONLIN.

A validated LC-MS assay for SL-CBZ, CBZ and their respective epoxidemetabolites was used. Carbamazepine-d.sub.10 (CBZ-d₁₀, C/D/N Isotopes,Quebec, Canada) was used as the internal standard. CBZ was assayedsimilar to that described by Osterloh and Bertilsson. (Oster-loh J,Bertilsson L. The absence of isotopic effect during the elimination ofdeuterium labeled carbamazepine in the rat. (Life Sci. 1978; 23:83-7.)To obtain a standard for CBZ-glucuronide, it was isolated from the urineof patients on CBZ monotherapy using a procedure similar to thatpreviously published. (Sinz M W, Remmel R P. Analysis of lamotrigine andlamotrigine 2-N-glucuronide in guinea pig blood and urine byreserved-phase ion-pairing liquid chromatography. J Chromatogr 1991;571:217-30) A 0.5 ml aliquot of patient plasma and 10 microliters ofinternal standard was added to blank plasma and extracted with 3 volumesof ethyl acetate. After shaking and centrifugation, the organic layerwas removed and evaporated under nitrogen gas to dryness. Each samplewas then redissolved with the addition of 25 microliters of ethylacetate. Plasma samples were measured for unbound and total CBZ, CBZglucuronide and CBZ-E by LCMS. Unbound drug was separated from the boundfraction by ultrafiltration. The mobile phase consists of 50% 0.05 Mammonium acetate buffer, pH 4.7, 50% MeOH at a flow rate of 0.4 ml/min,on a reverse phase C-18 column. For selected ion monitoring (SIM),signals at m/z 237 (CBZ), 239 (¹³C¹⁵N₂-CBZ), 253 (CBZ-epoxide), 255¹³C¹⁵N₂-CBZ-epoxide) and 247 (CBZ-d₁₀) were measured with a PC-basedHewlett-Packard Chem-Station® software. The lower limit of detection is0.05 micrograms/ml for CBZ. LC-MS method has been validated for thedetermination of [¹³C,¹⁵N]-carbamazepine, carbamazepine, and their10,11-epoxide metabolites in human plasma. Over a concentration range of1.5 to 12 micrograms/ml the percent coefficient of variance was ≦5%.

Table 3 provides the pharmacokinetic parameters for 76 subjects. Therange of oral CBZ daily dose ranged from 100 mg to 2400 mg for subjectsin this study. As can be seen, the absolute bioavailability of oral CBZduring maintenance therapy centers around 70-75% with 30 of the 56subjects having bioavailabilities below 70%. The variability ofbioavailability is also substantial with a range of 0.35 to 1.65. Thehighly variable bioavailability could be indicative of delayed releaseof drug from the various immediate and extended release oralformulations of CBZ or from continued absorption from an extendedrelease dosage form into a subsequent dosing interval. The distributionvolume at steady state (VSS) is 1.24±0.439 L/kg. This is a previouslyunknown value (due to the lack of an IV formulation) the now permitsprecise dosing of an IV formulation to attain a targeted plasma CBZconcentrations as might be required when initiating therapy in patientswhose oral therapy has been interrupted for 12 or more hours.

Another clinically important observation is the prolonged CBZelimination half-life under steady-state conditions. The mean value wasdetermined to be 25.8 hours (range from 8.79 to 64.6 hours) in contrastwith the reported range of 12 to 17 hours in the package insert forTegretol° and Carbatrol°. The most likely explanation for thisdifference is the use of an SL-IV CBZ solution in the present study thatpermitted rigorous characterization of elimination for 2-3 half-liveswhile subjects continued to take their oral CBZ doses as prescribed. Theextended half-lives observed in the adult subjects will limit thefluctuation of CBZ concentrations following IV administration every sixhours, further reducing the risk of sub-therapeutic CBZ concentrations.

TABLE 3 Carbamazepine Summary Pharmacokinetics AUCss AUC Body (po) 0-°oWeight T½ (μg- (μg- VSS CL CLSS/F Age (yr) (kg) F (hr) hr/mL) hr/mL)(L/kg) (L/hr/kg) (L/hr/kg) N 76 76 70 76 70 76 76 76 70 Mean 46.9 81.70.742 25.8 89.5 38.2 1.24 0.040 0.045 (SD) (15.7) (17.7) (0.29) (11.2)(29.3) (15.3) (0.439) (0.015) (0.024) Min 19.0 48.0 0.348 8.79 28.5 14.90.612 0.013 0.0087 Median 45.0 82.0 0.670 24.6 87.2 36.5 1.13 0.0360.041 Max 87.0 151 1.65 64.6 168 94.5 3.17 0.089 0.122 Note: The valuesof F, AUCss (po), and CLss/F included only 70 subjects due to 6 subjectsonly receiving the morning IV dose of CBZ. The range of oral CBZ dailydose ranged from 100 mg to 2400 mg.

The present study utilized the 2-hydroxypropyl-β-cyclodextrinformulation for a drug solubilizing agent of SL-CBZ. The pharmacokineticdata obtained from this study, while not specifically designed todetermine a full replacement IV dosing regimen, can assist inestablishing the target dose for this study. The results from thepresent study demonstrate a wide range of CBZ bioavailability valuesamong subjects, several of which had calculated bioavailability valuesgreater than 100%. As a result, a bioavailability value of 70% has beenchosen for use when dosing subjects in this sequential study. This valueis similar to the median F value (67%) determined from subjectsadministered IV CBZ in the present study (n=76). The justification forusing the median bioavailability value for correcting the dose for IVadministration of CBZ in the current study assumes that the truebioavailability in subjects should not be greater than 100% especiallyat steady-state dosing levels. The value of 70% is between thecalculated mean F value of 75% and the true rank order median value of67%, and allows for an appropriate, calculable IV dose adjustment. Thetypical subject should then receive a daily IV dose that is 70% of thatindividual's daily oral dose. This can produce CBZ plasma concentrationsfrom the IV dose that are comparable to those concentrations resultingfrom oral administration in the majority of subjects. Thus, the resultsof the present study provide initial safety and tolerability of acarbamazepine-cyclodextrin combination in subjects along with providingdata that can be used to calculate the appropriate dose and dosinginterval for replacement IV therapy.

Example 4 Preparation of CBZ Standard Solution Equipment

Shimadzu HPLC systems with autosampler, pumps, degassers, UV detector,column oven, system controllers, and Shimadzu Class VP system Software

-   Cahn Microbalance

Shimadzu AY-120 Analytical balance pH meter, Orion pH/ISE Model #420 A

-   LabnetVX 100 Vortex-   Eppendorf Centrifuge 5415 D-   Fisher Scientific FS30 Sonicator-   LabQuake Shaker-   Materials

Material Manufacturer Lot No. Carbamazepine Spectrum SA0491Carbamazepine Orgamol 899954 Cavitron Cargill H3M134P 82004 CaptisolCydex CY03A020535 Acetonitrile Fisher 031168 Purified waterPreparation of CBZ Standard Solution (0.05 mg/L)

Weigh out 5 mg of CBZ and place in a 100 ml volumetric flask. Fill tovolume with 60% aqueous acetonitrile.

Preparation of Cyclodextrin Vehicles

The percent weight/volume cyclodextrin solutions were prepared by addingthe appropriate amount of cyclodextrin to a flask and filling to thedesired total volume (10 mL) with water, as shown in the following Table4.

TABLE 4 Amount of Cyclodextrin (g) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.04.5 5.0 6.0 7.0 8.0 9.0 Cyclodextrin in 0 5 10 15 20 25 30 35 40 45 5060 70 80 90 Water % (w/v)In initial assays, the flasks were graduated cylinders. In subsequentassays, the cyclodextrin was first dissolved in a small volume of water,quantitatively transferred to a volumetric flask which was then broughtto volume with water.

Preparation of Samples for Phase Solubility

An excess of carbamazepine was added to each eppendorf tube. Appropriatevehicles were added to each tube and the final volumes were 1 mL.

Example 5 Phase Solubility

The solubility of CBZ was determined at ambient laboratory temperaturesin various concentrations of aqueous Captisol and aqueous Cavitron(brand names of modified cyclodextrins useful in the present invention).The drug substance was added to a microcentrifuge tube and theappropriate vehicle was added. Periodically, the samples werecentrifuged and then an aliquot was removed from the supernatant,diluted as necessary and assayed by HPLC to determine the concentration.The phase solubility was evaluated at least three times during eachexperiment to insure that the mixture achieved equilibrium. In general,the early concentration determination data (obtained approximately 2hours after mixing the CBZ and the vehicle) were omitted because CBZappeared to form supersaturated solutions initially beforeequilibration. The solubilities reported in Table 5 are the average oftwo or three concentration determinations obtained during the respectivetime course.

TABLE 5 Phase solubility data for CBZ in the presence of varyingcyclodextrin concentrations Cyclodextrin Captisol Cavitron CBZ sourceSpectrum Orgamol Orgamol Spectrum Orgamol Orgamol Cyclodextrin MeasuredCBZ conc % Measured CBZ conc % conc (% w/v) (mg/mL) Ave S.D. R.S.D.(mg/mL) Ave S.D. R.S.D. 0 0.2 0.2 0.2 0.2 0.0 0.0 0.3 0.2 0.2 0.2 0.013.3 5 2.4 2.2 2.4 2.3 0.1 4.9 3.8 2.7 3.0 3.2 0.6 18.0 10 6.2 4.1 4.65.0 1.1 22.1 4.1 5.4 5.6 5.0 0.8 16.2 15 6.9 6.4 7.7 7.0 0.7 9.4 12.38.2 8.4 9.6 2.3 24.0 20 9.4 9.2 10.3 9.6 0.6 6.1 16.4 10.9 11.1 12.8 3.124.4 25 11.8 11.4 12.3 11.8 0.5 3.8 14.8 14.0 14.3 14.4 0.4 2.8 30 14.613.5 15.2 14.4 0.9 6.0 17.9 15.9 16.2 16.7 1.1 6.5 35 16.3 15.9 18.416.9 1.3 8.0 20.7 18.1 19.9 19.6 1.3 6.8 40 19.3 18.3 20.8 19.5 1.3 6.523.2 22.5 22.0 22.6 0.6 2.7 45 21.8 20.6 22.5 21.6 1.0 4.4 27.3 25.525.7 26.2 1.0 3.8 50 26.6 22.5 24.8 24.6 2.1 8.3 31.5 27.8 28.0 29.1 2.17.3FIG. 1A shows a graphical representation of the compiled solubilitydata. From these data, it appears that the CBZ solubility at mostcyclodextrin concentrations is marginally improved in Cavitron, ascompared to Captisol. FIG. 1B shows the averaged solubility data withthe associated standard deviations. The latter Figure also provides thetrend lines for the averaged data.

Binding Constant

Assuming a 1:1 complex forms, the binding constant K_(1:1) can becalculated, according to the relationship:

K _(1:1)=slope/[S ₀(1−slope)]

where S.sub.0 is the intrinsic solubility. The phase solubility datawere expressed in terms of molarity and the equations of the lines were:

Captisol: y=0.4379x+0.0008r ²=0.9989

Cavitron: y=0.3515x+0.0008r ²=0.9954

From these equations, the binding constants of Captisol:CBZ andCavitron:CBZ were found to be 974 and 677 M⁻¹, respectively. Theserelatively weak associations are within the range (100-20,000 M⁻¹) ofthose commonly seen with drug: cyclodextrin complexes (Crit. Rev. Ther.Drug Carrier Systems, 14 (1): 1-104, 1997). Stella et al. simulated drugrelease from cyclodextrins upon dilution (Advanced Drug Del. Rev. 36,3-16, 1999) and suggested that if complexes are diluted 100-fold in theabsence of any endogenous competing agent, approximately 30% of the drugwill remain complexed, and if they are diluted 1000-fold, approximately5% of the drug will remain complexed.

The minimal volume of distribution of a drug administered intravenouslyis based on the plasma volume, which is approximately 5% of the bodyweight. Therefore, in a 70 kg subject, the plasma volume isapproximately 3.5 L. Alternatively, one could assume that the volume ofdistribution is extracellular water, accounting for approximately 30% ofthe total body weight, in which case the volume of distribution is about21 L.

Table 6 shows the theoretical dilutions that would result from a 25mg/mL formulation administered at different dose volumes. Thesecalculations do not assume that any endogenous compounds might displaceCBZ, and so they can be considered to be very conservative estimations.If a 20 mL dose were administered, the dilution ranges from175-1,050-fold.

Based on the simulations of dilution effects, it appears that 70-95% ofthe CBZ will immediately dissociate from the inclusion complex in theblood if one assumes no interaction from endogenous agents.

TABLE 6 Theoretical extent of dilution for a 25 mg/mL CBZ formulationCBZ dose, mg 200 500 800 Total dose 8 20 32 volume, mL Extent ofDilution Plasma volume, 438 175 109 3,500 ml. Extracellular 2,625 1,050656 volume, 21,000 mL

Method of Vehicle Preparation

The phase solubility data from the first set of assays performed usingthe two cyclodextrins appear to be higher than all of the subsequentphase solubility experiments (data not shown). In this first assay, thecyclodextrin solutions were prepared by weighing the appropriate amountof cyclodextrin and adding it to a graduated cylinder and mixing todissolve the solid. In all subsequent assays, the appropriate amount ofcyclodextrin was added to a vial, dissolved, quantitatively transferredto a volumetric flask, filled to volume with water and mixed. Thissecond method of vehicle preparation is more accurate and apparentlysignificantly influenced the resulting phase solubility data. However,it is very difficult to prepare the cyclodextrin solutionsvolumetrically.

Effect of Cooling Saturated Solutions at 2-8° C.

The saturated CBZ/cyclodextrin solutions were placed in a 2-8° C.refrigerator and the appearances were recorded at various times. At 24hours, all of the solutions showed a precipitate.

Example 6 Thermal Analysis

CBZ is known to exist in at least four different polymorphic states (J.Pharm. Sci. 90, 1106-1114, 1990). At one point in this study, it wassuspected that the variability in the solubility data might be due topolymorphic differences. Thermal analyses using differential scanningcalorimetry (DSC) and thermogravimetric analysis (TGA) were performed onthe Spectrum CBZ and the Orgamol CBZ to determine if there weredifferent polymorphs present in each product. Table 7 summarizes theexperimental conditions and the thermal data.

TABLE 7 Thermal transitions obtained for CBZ from two manufacturers.Thermogravimetric analysis Differential scanning Ramp 10° C./mincalorimetry from 25° C. to Ramp 5° C./min From 25° C. 400° C. to 300° C.Initial Sample Onset All Onset AH Vendor weight % weight weight peak 1Peak 1 Peak 1 peak 2 Peak 2 Peak 2 Lot-Batch # (mg) loss (mg) (° C.) (°C.) (1/g) (° C.) (° C.) (1/g) Orgamol 9.687 87.25 3.246 161.92 165.2514.03 183.22 185.70 117.2 899954 Spectrum 5.351 100.1 4.510 157.7 164.3810.62 189.53 190.25 127.3 SA0491

Example 7 Appropriate Dosing Interval Determination

The most relevant factor in considering the dose adjustment forintravenously administered CBZ is for treatment centers to maintainplasma concentrations of CBZ above the therapeutic threshold. Followingadministration of 100 mg of IV CBZ, observed plasma concentrationsfollowed a tri-exponential decay indicating a very fast distribution totissues followed by a slower elimination of drug out of the body.Steady-state plasma concentrations of IV CBZ were predicted using themethod of superposition. Plasma concentrations following a single doseof IV CBZ were scaled-up to steady-state conditions, assuming linearpharmacokinetics, using an accumulation ratio, a mean F of 0.7, andcorrecting for dose (see Equations 1 and 2). As a result, thiscalculation allows for a comparison of steady-state trough plasmaconcentrations following oral (C_(o) and IV (C_(6 hr)) administration ofCBZ respectively assuming a dosing interval of once every six hours forthe IV formulation.

$\begin{matrix}{F = {\frac{{AUC}_{r,{ss}}({Oral})}{{AUC}_{0 - \infty}({IV})} \times \frac{{Dose}({IV})}{{Dose}({Oral})}}} & {{Equation}\mspace{14mu} 1} \\{{C_{pSS}({IV})} = {{{C_{pSD}(t)}({IV})} + {\frac{{Int}\; \exp^{{- \lambda}\; T}\exp^{{- \lambda}\; T}}{1 - \exp^{{- \lambda}\; T}} \cdot \frac{\left( {D_{po}F} \right)}{D_{IV}4}}}} & {{Equation}\mspace{14mu} 2}\end{matrix}$

Where C_(pss)(IV) is the plasma concentration (C) at steady state for IVadministration; C_(pSD) is the plasma concentration after a single dose;Int is the y-intercept resulting from linear regression of theelimination phase; λ is the terminal elimination rate constant; D_(po)is the total oral daily dose; D_(IV) is the single IV dose; F is theabsolute bioavailability; T is the dosing interval; and t is the time ofeach observed concentration.

The observed mean, oral steady-state trough (C_(o)) plasma concentrationof CBZ following twice daily dosing was 8.98 (μg/mL (n=62 evaluablesubjects) (see Table 8, “Statistical Comparison of Trough Steady-StateCarbamazepine Concentrations Following Oral BID Dosing or Q6 IV DosingBased on Mean F=0.70”). The mean steady-state plasma concentration atthe 6-hour time-point following IV administration of CBZ was predictedto be 8.04 (μg/mL. Statistical comparison of these two trough valuesfollowing oral and IV administration of CBZ was found to be notstatistically different (α=0.10; p=0.1931). Thus, the dosing frequencyof every six hours following IV administration of CBZ outlined isappropriate to maintain plasma concentrations above this threshold andbe comparable to trough levels following oral administration. Analysisof the same parameters at the 12-hour time-point, post-dose, indicatedthat the trough values were significantly different suggesting that anIV dosing regimen of every 12 hours would not be feasible to ensure theplasma concentration of CBZ does not fall below the therapeutic range.

TABLE 8 Statistical Comparison of Trough Steady-State CarbamazepineConcentrations Following Oral BID Dosing or Q6 IV Dosing Based on Mean F= 0.70 Differ- SE ence for the Be- Differ- 90% CI for tween ence theCarbamazepine the in the Difference in p- Concentration N Mean MeansMeans the Means value C_(o) 62 8.98 0.09456 0.7158 (−0.254, 2.15) 0.1931(oral only) C₆ hr (IVonly)- 62 8.04 Mean F)

Example 8 Anticipated CBZ Maximum and Minimum Concentration ValuesDuring Intravenous Administration: Subjects at the Extreme ofCarbamazepine Bioavailability

A subset analysis of the subject data (n=47), including only thosesubjects taking extended release (ER) formulations of CBZ twice daily(as indicated by the product label), was performed to compare predictedmaximum and minimum exposures of CBZ at steady-state administered via IVinfusion to those observed following oral administration. CBZconcentration-time profiles following IV administration will differ fromoral administration to the greatest extent for subjects on ER products,since these products provide formulation dependent control of theconcentration-time profile. Subjects on extended release formulationsexperience the least fluctuation in concentrations and will maintainhigher relative trough concentrations compared to any non-extendedrelease product. Thus, the analysis in this subset gives a conservativeassessment of potential differences in peak and trough exposuresfollowing IV administration.

This analysis included calculations of predicted C_(max), C_(min), andAUC_(ss) values of CBZ for subjects predicted to be at steady-state onIV therapy. In order to predict steady-state plasma concentrations of IVCBZ, the same procedure for scaling plasma concentrations of CBZ asstated previously was implemented using Equations 1 and 2. Linearpharma-cokinetics were assumed and plasma concentrations following asingle 100 mg dose of IV CBZ were scaled-up to steady-state conditionsusing an accumulation ratio (determined using each individual's terminalelimination rate constant), and assuming a mean F of 0.7 for computationof the IV dose administered.

Following scale-up of the plasma concentrations of CBZ to steady-state,summary statistics of pharmacokinetic parameters were reported tocompare the range of CBZ C_(max), C_(min), and AUC values between theoral (observed) and IV formulations of CBZ assuming a bioavailability(F) of 0.7 (See Table 9, “Summary Statistics of Predicted Steady-StateParameters Following Administration of IV or Oral Carbamazepine”). Thesteady-state PK parameters for the oral and IV formulations wereobtained from data within the 12 hour dosing interval followingadministration of the ER products (Carbatrol.®. and Tegretol XR.®.) orthe 6 hour interval after dosing of the IV product, respectively.

TABLE 9 Summary Statistics of Predicted Steady-State ParametersFollowing Administration of IV or Oral Carbamazepine Mean ± 5^(th)95^(th) PK SD Minimum Percentile Median Percentile Maximum Parameter N(μg/mL) (μg/mL) (μg/mL) (μg/mL) (μg/mL) (μg/mL) IV 47 11.75 ± 7.90  3.174.80 9.93 24.14 47.0 C_(max)SS (mean F = 0.7) IV 47 8.63 ± 6.85 1.652.48 6.50 18.64 41.04 C_(min)SS (mean F = 0.7) IV 47 121.83 ± 90.93 26.88 43.10 93.69 257.16 551.11 AUC_(SS) (mean F = 0.7) Oral 47 9.92 ±2.99 2.89 4.98 9.81 14.60 17.10 C_(maxss)* Oral 47 9.32 ± 2.93 2.89 4.329.44 14.55 16.69 C_(minss)* Oral 47 96.79 ± 28.08 28.48 50.11 96.01145.51 167.58 AUC_(ss) *Oral Cmax, ss estimate is based on highestobserved concentration, and may not be indicative of the subjects trueCmax, ss value due to sparse sampling; this study was not designed toassess the Cmax, ss of oral CBZ. *Oral Cmax, ss estimate is based onhighest observed concentration, and may not be indicative of thesubjects true Cmax, ss value due to sparse sampling; this study was notdesigned to assess the Cmax, ss of oral CBZ.

The scaled-up steady-state CBZ concentrations were predicted based upona 100 mg single IV dose infused over 10 minutes. The mean steady-stateIV C_(max), value was 11.75 (μg/mL, a plasma level that is highercompared to the mean oral C_(max) at steady-state (see Table 9). Giventhe wide range of individual subject bioavailability values (F values)(see Table 3), subjects taking high doses of oral CBZ and subjects atthe extreme lower end of bioavailability may experience maximum plasmaconcentrations of CBZ that are in excess of the reported therapeuticrange for this compound (see Table 9). Subjects taking high doses oforal CBZ compounded with an inherent low bioavailability could be at thegreatest risk for adverse effects due to elevated CBZ plasma levels. The70% dose adjustment would be the standard across all subjectsadministered replacement IV CBZ therapy to ensure the majority ofsubjects stay above the minimum (trough) therapeutic threshold and thuspreventing seizures. If a subject's true bioavailability is less thanthe F value used for dosing, drug accumulation will occur when theinclusion complex is administered intravenously.

Example 9 Modeling and Simulation to Assess the Effect of InfusionDuration on Cmax,ss Following Administration of IntravenousCarbamazepine

CBZ bioavailability is extremely variable among subjects andcomplicating factors such as formulations with different release rates,doses, and dosing intervals add to an already complex pharmacokineticprofile. Systemic exposures after IV administration of CBZ will not varyamongst subjects to the extent that systemic exposures vary after oraladministration, since formulation characteristics and bioavailabilityare excluded as sources of variability following IV administration. Doseadjustments in subjects for IV CBZ replacement therapy must protectagainst low plasma concentration levels possibly leading to an increasedrisk in break through seizures. Concurrently, the effects of increasedtransient CBZ exposures can occur in some subjects at the extreme lowend of oral bioavailability or distribution volume.

The scaled IV CBZ concentration-time curves from the pharmacokineticdata of subjects dosed over 10 minutes reveal that the frequencydistribution of C_(max) values is unequal with a skewed tail at theextreme high end of C_(max) values. At a mean bioavailability value forthe population assigned to 70% (as is appropriate for the dosing in thepresent invention), the mean population C_(max) value was 11.75 μg/mLwith a median value of 9.93 μg/mL. The 95th percentile C_(max) value was24.14 μg/mL with a range of C_(max) values from 3.17 μg/mL to 47.00μg/mL (See Table 9, “Summary Statistics of Predicted Steady-StateParameters Following Administration of IV or Oral Carbamazepine”).

To assess the effect of infusion duration on C_(max,ss) modeling andsimulation was performed using the observed plasma concentrations of CBZfollowing IV administration of the single 100 mg dose. Based on variousdiagnostic plots assessing goodness-of-fit of the PK model, plasmaconcentrations of CBZ were best described by a three-compartment model,displaying a very rapid tissue distribution phase indicative of highlyperfused tissues such as the liver, lung and brain, a seconddistribution phase indicative of deeper tissue penetration such asadipose tissue, and a more prolonged elimination phase (FIG. 4). Themodeling results revealed that the mean t1/2 (α) and t1/2 (β) were rapid(approximately 2 minutes and approximately 65 minutes, respectively),indicating that elevated plasma levels of CBZ will be short-lived oncean infusion is stopped. Population mean terminal t1/2 (γ) isapproximately 28 hours, which is comparable to the value based onnoncompartmental analysis (Table 3). Assuming that the pharmacokineticsare linear and stationary, using each subject's predicted parametersfrom the PK model, simulations were performed at steady-state todetermine the effect of infusion duration on CBZ C.sub.max, ss (FIG. 5).The results showed a decrease in the mean C_(max,ss) as the infusionduration increased (based upon a mean IV dose of 150 mg when dosed understeady state conditions). The mean, modeled C_(max,ss) value after a 60minute infusion was 10.68 μg/mL compared to 10.04 μg/mL after a 30minute infusion compared to 11.69 μg/mL after a 15 minute infusion.

There was only an approximate 135 decrease in the mean C_(max ss) valuewhen the infusion duration was increased from 15 minutes to 1 hour.

Notably, the peak concentration from the typical value simulation (150mg IV dose) shown in FIG. 5 is comparable but differed slightly to thatof the scaled, observed IV C_(maxss) reported in Table 9 (approximately9.50 μg/mL and 11.75 μg/mL respectively). The model dependent prediction(FIG. 6) more accurately captures the time point of the true maximumconcentration, whereas the scaled, observed value (Table 9) is dependentupon the time of collection. The median (maximum) elapsed time betweenthe end of infusion and the next time of collection was 5.3 (38.0)minutes. With t1/2 (α) of 2.2 minutes, considerable decay inconcentration will occur during this time. For the full population, theactual median (maximum) time to observed C_(max,ss) after the end ofinfusion was 5.8 (240) minutes. Additionally, all modeled infusions wereprecisely of 15 minutes duration. If actual infusion durations weregreater than 15 minutes, C_(max,ss) would be lower than predicted by themodel. Finally, the typical value prediction modeled in FIG. 5 used eachindividual's set of model parameters and a typical dose (150 mg, theaverage adjusted IV dose assuming F=0.70), where the scaled observedvalues are based on the range of individual doses along with applyingthe superposition method at each observed concentration. As shown inFIG. 6, the average C_(max,ss) values are similar with a 30 minute and60 minute infusion.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all the changes which come within the meaning and rangeof equivalency of the claims are therefore intended to be embracedtherein.

We claim:
 1. A method of administering carbamazepine to a mammal in needthereof comprising, parenterally infusing into the mammal acarbamazepine sulfoalkyl-cyclodextrin composition, wherein thecomposition comprises about 10 mg/mL carbamazepine, about 25%weight/volume sulfobutylether-7-β-cyclodextrin, and a physiologicallyacceptable fluid.
 2. The method of claim 1, wherein the mammal has aseizure disorder.
 3. The method of claim 2, wherein the seizure disorderis partial seizures with complex symptoms, generalized tonic-clonic(grand mal) seizures, mixed seizure patterns, epilepsy, statusepilipticus, refractory seizure disorders or a combination thereof. 4.The method of claim 3, wherein the seizure disorder is epilepsy.
 5. Themethod of claim 3, wherein the seizure disorder is status epilipticus.6. The method of claim 1, wherein the composition is administeredintravenously, intraarterially, intramuscularly, subcutaneously orintraperitonealy.
 7. The method of claim 6, wherein the composition isadministered intravenously.
 8. The method of claim 1, wherein the mammalis a human.
 9. The method of claim 1, wherein the composition isadministered as a replacement for oral carbamazepine.
 10. The method ofclaim 9, wherein the carbamazepine sulfoalkyl-cyclodextrin compositionis administered in a daily dosage of about 65% to 75% of the mammal'sdaily oral carbamazepine dosage.
 11. The method of claim 1, wherein themammal has trigeminal neuralgia, glossopharyngeal neuralgia, neurogenicdiabetes insipidus, schizoaffective illness, depression, agitation,behavioral disturbances related to dementia, resistant schizophrenia,dyscontrol syndrome associated with limbic system dysfunction, alcoholwithdrawal, fibromyalgia, neuropathy, or a combination thereof.
 12. Themethod of claim 1, wherein the mammal has trigeminal neuralgia orfibromyalgia.
 13. The method of claim 2, wherein the mammal hastrigeminal neuralgia.
 14. A method of administering carbamazepine to ahuman in need thereof comprising, intravenously infusing into the humana carbamazepine sulfoalkyl-cyclodextrin composition, wherein thecomposition comprises about 10 mg/mL carbamazepine, about 25%weight/volume sulfobutylether-7-β-cyclodextrin, and a physiologicallyacceptable fluid.
 15. The method of claim 14, wherein the human has aseizure disorder.
 16. The method of claim 15, wherein the seizuredisorder is partial seizures with complex symptoms, generalizedtonic-clonic (grand mal) seizures, mixed seizure patterns, epilepsy,status epilipticus, refractory seizure disorders, or a combinationthereof.
 17. The method of claim 16, wherein the seizure disorder isepilepsy.
 18. The method of claim 16, wherein the seizure disorder isstatus epilipticus.
 19. The method of claim 14, wherein the compositionis administered as a replacement for oral carbamazepine.
 20. The methodof claim 19, wherein the composition is administered in a daily dosageof about 65% to 75% of the human's daily oral carbamazepine dosage. 21.The method of claim 14, wherein the human has trigeminal neuralgia,glossopharyngeal neuralgia, neurogenic diabetes insipidus,schizoaffective illness, depression, agitation, behavioral disturbancesrelated to dementia, resistant schizophrenia, dyscontrol syndromeassociated with limbic system dysfunction, alcohol withdrawal,fibromyalgia, neuropathy, or a combination thereof.
 22. The method ofclaim 21, wherein the human has trigeminal neuralgia or fibromyalgia.23. The method of claim 22, wherein the human has trigeminal neuralgia.24. A method of administering carbamazepine to a human in need thereofcomprising, intravenously infusing into the human a carbamazepinesulfoalkyl-cyclodextrin composition, wherein the composition comprisesabout 10 mg/mL carbamazepine, about 25% weight/volumesulfobutylether-7-β-cyclodextrin, and a physiologically acceptablefluid, and wherein the human has epilepsy, status epilipticus,trigeminal neuralgia, fibromyalgia, or a combination thereof.
 25. Themethod of claim 24, wherein the human has epilepsy.
 26. The method ofclaim 24, wherein the composition is administered as a replacement fororal carbamazepine.
 27. The method of claim 24, wherein the human hasstatus epilipticus.
 28. The method of claim 25, wherein the compositionis administered as a replacement for oral carbamazepine.
 29. The methodof claim 24, wherein the human has trigeminal neuralgia.
 30. The methodof claim 24, wherein the human has fibromyalgia.